Current evidence suggests that permeability changes in the vascular lining occur much earlier than detectable lesions during the course of experimentally induced atherosclerosis. The aim of this proposal is to study vascular changes in rabbits fed cholesterol diets, using horseradish peroxidase as a tracer to detect early changes which would otherwise pass unnoticed. Horseradish peroxidase not only provides a way of assessing permeability but also makes it possible to identify non-viable cells and changes in the elastic laminae of arteries. Specimens of aorta and coronary arteries will be examined with the light microscope and transmission electron microscopy. The circulating monocyte appears to be among the earliest cells to concentrate cholesterol and to increase in number as circulating foam cells. In addition to lesion development, the appearance of foam cells in circulating blood will be correlated with plasma levels of cholesterol and beta lipoproteins. These methods, hopefully, would reveal the earliest changes which signal the onset of the disease as well as extend present knowledge of the development of the atherosclerotic plaque, including the participation of the various components of the vascular wall.